Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0085632 (apathy)
4,089 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Salt wasting syndrome is caused by a congenital or acquired synthesis disorder or by the aldosterone function disorder. It manifests itself by ionic disorders where the sodium and chlorine level decrease with the simultaneous potassium retention. Synthesised aldosterone is in the glomerular zone of the adrenal cortex. Symptoms of dyselectrolitemia are not distinctive, they develop within a few first days of life. The suction aversion, apathy, lack of growth or progressing, body mass loss is being noticed. The most often cause of salt wasting syndrome is the congenital cortical adrenal hyperplasia (CAH) caused by 21-hydroxylase enzyme deficit. The classic form with and without salt wasting (SW), as well as non-classic form is distinguished. The therapy of SW form depends on Hydrocortisone and Cortineff administering. The other forms of salt wasting syndrome occur not so often and these are: aldosterone synthesis deficit, dehydrogenase 3beta-hydroxysteroid deficit, lipoid cortical hyperplasia, adrenal hypoplasia congenital (AHC), adrenoleukodystrophy and pseudohypoaldosteronism. The knowledge of the symptoms and causes of salt wasting syndrome allows for the proper therapeutic management and contributes to the regular psychophysical infantile development of the children.
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PMID:[Salt wasting syndrome caused by congenital, insufficient synthesis or aldosterone function--etiology, diagnosis and management]. 1599 40

A 70-year-old patient treated with oxcarbazepine experienced severe hyponatremia. The patient used oxcarbazepine (600 mg twice a day) concomitantly with diuretics (torasemide 10 mg and indapamide 1.25 mg once per day), perindopril, an angiotensin-converting enzyme inhibitor, and amlodipine, a Ca(2+) channel blocker. The patient complained of a nausea, malaise, diplopia, drowsiness, apathy, decreased diuresis (creatinine clearance - 41.51 ml/min), and exacerbation of epileptic seizures. Sodium concentration in the plasma was 113 mmol/l. The patient was hospitalized. It was suggested that a decrease in plasma sodium concentration was caused by oxcarbazepine used together with diuretics for six months. Oxcarbazepine-induced hyponatremia is reported in 22.2-50% of patients, although symptoms are present only in 5.9% of patients. The most common symptoms of central nervous system injury, experienced by patients, are drowsiness, dizziness, decreased cognitive function, coordination impairment, etc. Physicians not always in time pay proper attention to undesirable antiepileptic drug-induced effects, which can be dangerous.
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PMID:[A case of severe hyponatremia in a patient suffering from epilepsy and using oxcarbazepine]. 1696 31

Congenital indifference to pain (CIP) is a rare condition in which patients have severely impaired pain perception, but are otherwise essentially normal. We identified and collected DNA from individuals from nine families of seven different nationalities in which the affected individuals meet the diagnostic criteria for CIP. Using homozygosity mapping and haplotype sharing methods, we narrowed the CIP locus to chromosome 2q24-q31, a region known to contain a cluster of voltage-gated sodium channel genes. From these prioritized candidate sodium channels, we identified 10 mutations in the SCN9A gene encoding the sodium channel protein Nav1.7. The mutations completely co-segregated with the disease phenotype, and nine of these SCN9A mutations resulted in truncation and loss-of-function of the Nav1.7 channel. These genetic data further support the evidence that Nav1.7 plays an essential role in mediating pain in humans, and that SCN9A mutations identified in multiple different populations underlie CIP.
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PMID:Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations. 1747 Jan 32

We measured voluntary water and sodium intakes of 40 inbred strains of mice. Groups of approximately 10 males and approximately 10 females from each strain received a series of 48-h tests with a choice between a bottle of water and a bottle of one of the following: water, 25, 75, and 225 mM NaCl, 25, 75, and 225 sodium lactate. Sodium solution intakes were influenced by strain, sex, anion and concentration: Nine strains drank significantly more chloride than lactate, and only one strain (I/LnJ) drank significantly more lactate than chloride. The other 30 strains drank similar volumes of chloride and lactate. Sodium intakes were higher in females than males of 8 strains and did not differ by sex in the other 32 strains. Some strains had consistently high sodium intakes and preferred all sodium solutions to water (129S1/SvImJ, MA/MyJ, NZW/LacJ and SWR/J), some showed indifference (i.e. preferences not significantly different from 50%) to all concentrations tested (A/J, C57BL/6J, FVB/NJ and SEA/GnJ), and some had consistently low sodium intakes (AKR/J, C3H/HeJ, C57BL/10J, CBA/J, DBA/2J, I/LnJ, JF1/Ms, LP/J, NON/LtJ, PERA/EiJ, PL/J, and RIIIS/J). The results illustrate the diversity of voluntary sodium intake in mice and will assist in the selection of appropriate strains for focused genetic and physiological analyses.
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PMID:Forty mouse strain survey of water and sodium intake. 1749 Jun 93

Understanding the role of voltage-gated sodium channels in nociception may provide important insights into pain mechanisms. Voltage-gated sodium channels are critically important for electrogenesis and nerve impulse conduction, and a target for important clinically relevant analgesics such as lidocaine. Furthermore, within the last decade studies have shown that certain sodium channel isoforms are predominantly expressed in peripheral sensory neurons associated with pain sensation, and that the expression and functional properties of voltage-gated sodium channels in peripheral sensory neurons can be dynamically regulated following axonal injury or peripheral inflammation. These data suggest that specific voltage-gated sodium channels may play crucial roles in nociception. Experiments with transgenic mice lines have clearly implicated Na(v)1.7, Na(v)1.8 and Na(v)1.9 in inflammatory, and possibly neuropathic, pain. However the most convincing and perhaps most exciting results regarding the role of voltage-gated sodium channels have come out recently from studies on human inherited disorders of nociception. Point mutations in Na(v)1.7 have been identified in patients with two distinct autosomal dominant severe chronic pain syndromes. Electrophysiological experiments indicate that these pain-associated mutations cause small yet significant changes in the gating properties of voltage-gated sodium channels that are likely to contribute substantially to the development of chronic pain. Equally exciting, recent studies indicate that recessive mutations in Na(v)1.7 that eliminate functional current can result in an apparent complete, and possibly specific, indifference to pain in humans, suggesting that isoform specific blockers could be very effective in treating pain. In this review we will examine what is known about the roles of voltage-gated sodium channels in nociception.
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PMID:The roles of sodium channels in nociception: Implications for mechanisms of pain. 1776 42

Gain-of-function mutations or dysregulated expression of voltage-gated sodium channels can produce neuronal hyperexcitability, leading to acute or chronic pain. The sodium channel Na(v)1.7 is expressed preferentially in most slowly conducting nociceptive neurons and in sympathetic neurons. Gain-of-function mutations in the Na(v)1.7 channel lead to DRG neuron hyperexcitability associated with severe pain, whereas loss of the Na(v)1.7 channel in patients leads to indifference to pain. The contribution of Na(v)1.7 to acquired and inherited pain states and the absence of motor, cognitive and cardiac deficits in patients lacking this channel make it an attractive target for the treatment of neuropathic pain.
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PMID:From genes to pain: Na v 1.7 and human pain disorders. 1795 Apr 72

Recent scientific advances have enhanced our understanding of the role voltage-gated sodium channels play in pain sensation. Human data on Nav1.7 show that gain-of-function mutations lead to enhanced pain while loss-of-function mutations lead to Congenital Indifference to Pain. Pre-clinical data from knockouts, anti-sense oligonucleotides, and siRNA for Nav1.3, 1.7, 1.8, and 1.9 have also demonstrated that specific subtypes of voltage-gated sodium channels play a role in different types of pain signaling. In addition, recent reports show that CNS penetration by voltage-gated sodium channel blockers is not required for efficacy in pre-clinical pain models while others have reported that identification of subtype-selective small molecules is possible. All of these data are converging to suggest next generation sodium channel blockers may offer the potential for novel pain therapies in the future.
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PMID:Sodium channels and nociception: recent concepts and therapeutic opportunities. 1796 52

Voltage-gated sodium (Na(V)1) channels play a critical role in modulating the excitability of sensory neurons, and human genetic evidence points to Na(V)1.7 as an essential contributor to pain signaling. Human loss-of-function mutations in SCN9A, the gene encoding Na(V)1.7, cause channelopathy-associated indifference to pain (CIP), whereas gain-of-function mutations are associated with two inherited painful neuropathies. Although the human genetic data make Na(V)1.7 an attractive target for the development of analgesics, pharmacological proof-of-concept in experimental pain models requires Na(V)1.7-selective channel blockers. Here, we show that the tarantula venom peptide ProTx-II selectively interacts with Na(V)1.7 channels, inhibiting Na(V)1.7 with an IC(50) value of 0.3 nM, compared with IC(50) values of 30 to 150 nM for other heterologously expressed Na(V)1 subtypes. This subtype selectivity was abolished by a point mutation in DIIS3. It is interesting that application of ProTx-II to desheathed cutaneous nerves completely blocked the C-fiber compound action potential at concentrations that had little effect on Abeta-fiber conduction. ProTx-II application had little effect on action potential propagation of the intact nerve, which may explain why ProTx-II was not efficacious in rodent models of acute and inflammatory pain. Mono-iodo-ProTx-II ((125)I-ProTx-II) binds with high affinity (K(d) = 0.3 nM) to recombinant hNa(V)1.7 channels. Binding of (125)I-ProTx-II is insensitive to the presence of other well characterized Na(V)1 channel modulators, suggesting that ProTx-II binds to a novel site, which may be more conducive to conferring subtype selectivity than the site occupied by traditional local anesthetics and anticonvulsants. Thus, the (125)I-ProTx-II binding assay, described here, offers a new tool in the search for novel Na(V)1.7-selective blockers.
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PMID:ProTx-II, a selective inhibitor of NaV1.7 sodium channels, blocks action potential propagation in nociceptors. 1872

Studies of genetic forms of epilepsy, chronic pain, and migraine caused by mutations in ion channels have given crucial insights into molecular mechanisms, pathogenesis, and therapeutic approaches to complex neurological disorders. Gain-of-function missense mutations in the brain type-I sodium channel Na(V)1.1 are a primary cause of generalized epilepsy with febrile seizures plus. Loss-of-function mutations in Na(V)1.1 channels cause severe myoclonic epilepsy of infancy, an intractable childhood epilepsy. Studies of a mouse model show that this disease is caused by selective loss of sodium current and excitability of GABAergic inhibitory interneurons, which leads to hyperexcitability, epilepsy, and ataxia. Mutations in the peripheral sodium channel Na(V)1.7 cause familial pain syndromes. Gain-of-function mutations cause erythromelalgia and paroxysmal extreme pain disorder as a result of hyperexcitability of sensory neurons, whereas loss-of-function mutations cause congenital indifference to pain because of attenuation of action potential firing. These experiments have defined correlations between genotype and phenotype in chronic pain diseases and focused attention on Na(V)1.7 as a therapeutic target. Familial hemiplegic migraine is caused by mutations in the calcium channel, Ca(V)2.1, which conducts P/Q-type calcium currents that initiate neurotransmitter release. These mutations increase activation at negative membrane potentials and increase evoked neurotransmitter release at cortical glutamatergic synapses. Studies of a mouse genetic model show that these gain-of-function effects lead to cortical spreading depression, aura, and potentially migraine. Overall, these experiments indicate that imbalance in the activity of excitatory and inhibitory neurons is an important underlying cause of these diseases.
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PMID:Inherited neuronal ion channelopathies: new windows on complex neurological diseases. 1900 38

Voltage-gated sodium channels have been implicated in acute and chronic neuropathic pain. Among subtypes, Nav1.7 single mutations can cause congenital indifference to pain or chronic neuropathic pain syndromes, including paroxysmal ones. This channel is co-expressed with Nav1.8, which sustains the initial action potential; Nav1.3 is an embrionary channel which is expressed in neurons after injury, as in neuropathic conditions. Few studies are focused on the expression of these molecules in human tissues having chronic pain. Trigeminal neuralgia (TN) is an idiopathic paroxysmal pain treated with sodium channel blockers. The aim of this study was to investigate the expression of Nav1.3, Nav1.7 and Nav1.8 by RT-PCR in patients with TN, compared to controls. The gingival tissue was removed from the correspondent trigeminal area affected. We found that Nav1.7 was downregulated in TN (P=0.017) and Nav1.3 was upregulated in these patients (P=0.043). We propose a physiopathological mechanism for these findings. Besides vascular compression of TN, this disease might be also a channelopathy.
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PMID:Abnormal expression of voltage-gated sodium channels Nav1.7, Nav1.3 and Nav1.8 in trigeminal neuralgia. 1969 81


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